TWI221842B - Process for the preparation of 8-azabicyclo(3.2.1)octane derivatives - Google Patents

Abstract

A process for preparing a compound of formula (IV), wherein R1 is C1-4 alkyl, CH2(C1-3 haloalkyl), benzyl, CH2(C2-5 alkenyl or CH2(C2-5 alkynyl), which comprises reducing a compound of formula (III). Compounds of formula (IV) are agrochemical intermediates.

Description

1221842

2. The present invention relates to a method for preparing 3-cyano-8-substituted azabicyclo [m] octane. 3-cyano-8-substituted κbicyclo [3 · 21] octane is used as an intermediate of specific insecticides (see, for example, WO 96/37494). The present invention provides a method for preparing a compound of formula (IV), wherein Ri is Cl_4 alkyl, alkyl), fluorenyl, CH2 (c2_5 alkenyl), or CH2 (C2_5 alkynyl) 'includes reducing the compound of formula (III). The reduction is preferably performed using an alcohol

(Jia Jia Methanol) and a suitable metal (such as magnesium), or in an alcohol (preferably methanol) and, if necessary, in the presence of a suitable amine (such as Edian), use a hafnium compound (4 such as Test metal borohydride), such as noodles or sodium hydrogen hydride; or through catalyst hydrogenation (such as using a catalyst containing palladium under appropriate pressure). -A specific aspect of the present invention is to provide a method for preparing a compound of formula (IV), wherein R1 is as defined above, including ... 1. dehydrating a compound of formula (Π) to obtain a compound of formula (III); and ii. Reduction Compounds of formula (III). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. For example, a compound of formula (II) in the presence of a suitable amine having a pKa of 3-11 (especially 4-6), if necessary, in a solvent, and a suitable temperature of 1 (rc (especially 10-40 ° C)), it can be dehydrated by using a suitable tritium base gas (such as thionine, phosphine, sulfonium chloride or carbochlorine); where the suitable amine is di ( CrC4 alkyl) amine (such as triethylamine or diisopropylethylamine), pyridine, (Ci 4 alkyl) pyridine (such as α-methylpyridine, β-methylpyridine, or cadaverine), (C i group) amine p ratio (such as 4-dimethylamino p ratio), Bilin, iso4-lin or bis (C 丨 _4 alkyl) aniline (such as n, N_dimethyl Aniline); 篸 Solution Celebrate ^ If it is an excessive amount of dioxin or heterogeneous—f ”capacitor or plate surname proton · _soluble genus” such as aromatic-4- This paper size applies Chinese National Standard (CNS) A4 specifications ( 21〇 > < 297 mm) 1221842 A7 B7 V. Description of the invention (2) Aromatic hydrocarbons (especially toluene, xylene, fluorobenzene or chlorobenzene) printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Acetonitrile, ether (especially tetrahydrofuran or dipurinane), or chlorinated lipid solvents (especially digas ethane). Preferably, the compound of formula (II) is in the presence of a suitable amine, preferably pyridine, Dehydration is performed using a suitable fluorenyl chloride (such as thionyl chloride or phosphonium chloride). Another aspect of the present invention provides a method for preparing a compound of formula (IV), wherein R1 is as defined above, including: i. Cyanation Compounds of formula (I) to produce compounds of formula (II); H. Dehydration of compounds of formula (II) to produce compounds of formula (III); and iii. Reduction of compounds of formula (III). Preferably, compounds of formula (I) In the presence of a suitable test, it is cyanated by reaction with hydrogen cyanide. Hydrogen cyanide is preferably prepared on the spot, for example by inorganic cyanide (such as metal cyanide 'such as sodium cyanide or cyanide) and Acids (such as organic acids (such as acetic acid) or strong inorganic acids (such as hydrochloric acid). Suitable bases include chloride anions, such as the presence of inorganic cyanides (such as alkali metal cyanides, such as sodium or potassium cyanide). Cyanation reaction can be in the presence of ammonium gasification The cyanation of the compound of formula (I) is preferably performed in the presence of a solvent or a mixture of solvents. The preferred solvent is water, and the preferred solvent mixture includes water and an ether (such as diethyl ether or methyl tertiary butyl ether), Alcohol (such as methanol or n-butanol) or a mixture of aromatic solvents (such as toluene). The alkyl group of R1 can be straight or branched, such as methyl, ethyl, n-propyl, or iso-propyl. The haloalkyl part of CH2 (CU3 haloalkyl) is preferably taken by gas or fluorine as required. ▲ Read the note on the back f · 丨 -Order 鲼 -5- This paper size applies to Chinese National Standards (CNS) A4 specification (210X297 mm) 1221842 A7 __________B7 V. Description of the invention (3) Substituted alkyl, such as 2,2,2-trifluoromethyl or 2,2-difluoromethyl. (Hence, CH2 (C 〖_3 haloalkyl) is, for example, 2,2,2-trifluoroethyl or 2,2-difluoroethyl). Alkenyl and decanyl are, for example, ethylene, allyl, or monopropyl. The compound of formula (II) can be obtained by adding a suitable inorganic cyanide (preferably potassium cyanide) to a compound of formula 及 and a suitable inorganic acid at a suitable temperature (preferably -20-20 ° C, for example, about 0 ° C). A mixture of (preferably hydrochloric acid or sulfuric acid), and optionally vaporized ammonium, and the reaction is carried out at this temperature. Suitable solvents for this reaction include water or a mixture of water and an organic solvent such as an ether (such as diacetic acid). In one aspect, the compound of formula (Π) can be prepared via the compound of formula (I) in the method described above, wherein an excess of hydrogen cyanide is used in the preparation. This excess can be achieved by using an excess (such as 1 to 2 (especially 1.1-1.8) equivalents) of acid and an excess (such as 1 to 2 (especially 1.1-1.6) equivalents) of inorganic cyanide. On the other hand, all the inorganic cyanide is added at the beginning of the preparation, and the acid is added throughout the preparation. Preferably, the acid is a strong inorganic acid (especially hydrochloric acid or sulfuric acid) and the inorganic cyanide is sodium cyanide or 4-methyl cyanide. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in yet another preferred aspect, the compound of formula (II) can be used in excess of the compound of formula (I) (for example, 1-10, especially 2.7 equivalents) of strong inorganic acid (Especially hydrochloric acid or sulfuric acid) and excess (such as 1-12, especially 3-8 equivalents) of metal cyanide (such as sodium cyanide or cyanide). This method is preferably performed at a temperature of -20-20 ° C, such as about 0 ° C. On the other hand, during the preparation of a compound of formula (II) at a suitable temperature (for example, -20-20 ° C, such as about 0 ° C), the compound of formula (I) and a suitable inorganic acid (preferably hydrochloric acid or sulfuric acid) The mixture is in a suitable solvent (preferably water), within a period of -6-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) " '1221842 A7 B7 V. Addition during the description of the invention (4) To inorganic cyanide (such as sodium cyanide or potassium cyanide). Please read the following precautions. The compound of formula (II) will degrade over time. Isolate the compound of formula (II) in a suitable organic solvent such as an ether such as diethyl ether or methyl tertiary butyl ether or an alcohol such as methanol or n-butyl ether. -Butanol) can minimize its degradation, and this solution can be used in the process of the compound of formula (II) acting as a compound of formula (III). Alternatively, the degradation of the compound of formula (II) can be minimized by adding a suitable stabilizer (such as Ua concentrated,% ii-acid J) before its isolation. The compound of formula (III) can be added to the compound of formula (II) to Phosphonium chloride and a suitable amine (such as pyridine) in a suitable solvent, and then the reaction is carried out at a suitable temperature (such as between 50 ° C and the boiling point of the solvent used), where the appropriate solvent can be an excess of phosphorus Chlorine, or when the amine is a liquid, it may be an excess of amine. For the degradation of the compound of formula (II), fluorenyl chloride is preferably added to the mixture of the compound of formula (II) and the amine, preferably < 20 ° C. The compound of formula (IV) can be added to a mixture of an alcohol (preferably methanol) and an appropriate amine (such as pyridine) by adding a compound of formula (III) and then an appropriate borohydride (especially sodium hydrogen) ·) To the reaction mixture, so that the reaction is performed at a suitable temperature (for example, between 50 ° C and the boiling point of the alcohol used). Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Z Alternatively, the compound of formula (IV) can be prepared by adding magnesium to a mixture of a compound of formula (III) and an alcohol (especially methanol) and maintaining the temperature at -20-20 ° C (especially about 0 ° c). Got. Alternatively, the compound of formula (IV) can be prepared by performing a catalyst hydrogenation in a solvent or a solvent mixture using a suitable catalyst (preferably free of carbon) at room temperature and atmospheric pressure under a compound of formula (III), wherein the solvent It is selected from water and alcohol (especially this paper size applies Chinese National Standard (CNS) 8.4 specification (210 x 297 mm) 5. Description of the invention (5) ethanol): Ge aromatic solvent (especially toluene). A suitable solvent is ethanol and water. Formaldehyde and water; toluene and methanol; or preferably, the compound of formula (IV) can pass the compound of formula _ at a substantial 0.5-5.0% λ ^^ μ ^ ^ 2 0_1〇〇〇c (= Γ75τ temperature And 1-10 bar (especially 2-6 bar) pressure and the presence of a solvent or other substances, the catalyst hydrogenation effect, in which the catalyst horse: barium acid on the carbon, E Huaming, Ming oxide, Raney nickel (R_y core on carbon (and ^ carbon is preferred). Preferred solvents are aromatic fluorene: M such as benzene, toluene, o-xylene, m-xylene or p-xylene) or aliphatic Alcohols (specifically C ,. 6 aliphatic alcohols, such as ethanol or tertiary τ alcohol), preferably the toluene is (or a mixture of 10: υ toluene and tertiary butanol. Another aspect of the present invention provides- A method for preparing a compound of formula (IV), wherein R1 is as defined above, including: i. At a room temperature, a compound of formula 与 is mixed with a metal oxide (such as sodium cyanide or potassium cyanide) and an inorganic acid ( Preferably, a mixture of hydrochloric acid or sulfuric acid is reacted to prepare a compound of formula (Π); ii. In the presence of pyridine, a compound of formula („) is reacted with sulfurous chlorine or phosphine gas Should be used to formulate compounds of formula (III); and iii. In substantially anhydrous conditions, 35-75. (: Temperature and pressure of 2-6 bar, in a palladium on carbon catalyst and aromatic hydrocarbon solvents (preferably (Toluene or xylene) in the presence of a compound of formula (III) and hydrogen to reduce it. Preferably, the amount of the mixture of the alkali metal cyanide and the inorganic acid in (1) relative to the compound of formula (I) has 3-10 equivalents of hydrogen cyanide. -8-1221842 A7 B7 5. Description of the invention (6) In the above method, R1 is CH2 (Ci · 3 haloalkyl), especially CH2CF3 or CH2CHF2. Compounds of formula (A) can be borrowed. It is prepared by reacting a compound of formula (IV) with compound R2L in the presence of appropriate tests, where R2 is an autogen, Cl_4 alkyl, Ci_4 alkoxy, cyano, c2 · 4fluorenyl, or c2_4 block if necessary. Substituted P is more than a base, and L is a suitable leaving group (for example, dentin or mesylsulfonyl). Therefore, 'another aspect of the present invention provides a compound of formula (A), It is prepared by reacting a compound of formula (IV) (prepared by the above method) with compound r2l. For compounds of formula (A), where Ri is Ci4 alkyl, CH ^ Cu haloalkyl), benzyl, CH2 (c2_5 alkynyl) or CH2 (c2 5 alkynyl), and R2 is halogen, Cl_4 , Ci4 alkoxy, cyano, C2_4 alkenyl or C2 · 4 alkynyl substituted pyridyl, which is prepared by a method comprising: i. Reducing a compound of formula (III) to obtain a compound of formula (IV), And 11. In the presence of a suitable test, react a compound of formula (IV) with compound r2l, where L is a suitable leaving group (such as halogen or mesylsulfonyl). The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed another aspect of the present invention to provide a compound of formula (11) or (111), wherein R1 is cN4 alkyl, ch2 (c 3 haloalkyl), benzyl, CH2 (C2_5 Fluorenyl) or CH2 (C2-5 block). Another aspect of the present invention provides a compound of formula (11) or (111), wherein R1 is 2,2,2-trifluoroethyl or 2,2-difluoroethyl. Another aspect of the present invention provides a method for preparing a compound of formula (11), wherein R is as defined above, and is included in a suitable solvent (such as water), and formula (V) is ____________ " (CNS) Meal Printed by the Consumers' Cooperative of the China Standard Associate Bureau of the Ministry of Economic Affairs

4: 8 1 2 12 A7 __________ B7___ 5. Description of the invention (8) liters). Add hydrochloric acid (5 ml, 5M), then add solid ammonium vaporization (2.15 g), stir the mixture until the ammonium chloride is dissolved, cool the mixture to 0 ° C, and potassium cyanide (5.031 g, 75 mmol) in water ( 7.5 ml) solution was added over 1 hour, and the final mixture was stirred at 0 ° C for 2 hours, during which a solid precipitate formed. The precipitate was separated by filtration and suction-dried for 10 minutes to obtain 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) -8-acid as an off-white solid (6.62 g). The second ring [3.2.1] was burned. Mass spectrometry data: 234 (M +), 217, 207, 178, 164, 150, 110 〇 Step 2 Printed and dried 100 ml three-necked round-bottomed flask printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics, connected to a reflux condenser, thermometer and magnetic The stirrer is filled with nitrogen. Phosphonium (8.89 g, 58 mmol) and pyridine (44 mL) were placed in a flask, and the mixture was cooled to -10 C in an acetone / DrikoldTM bath. Add a part of the 3- (3-, 2-)-yl 8- (2,2,2-trifluoroethyl) _8-acylbicyclo [3.2.1] octane (6.17 g, 26.4 mmol) ), And finally exothermic to raise the reaction mass temperature to 28 ° C. The mixture was heated to 80 ° C and maintained at this temperature overnight. When the reaction mass was cooled to room temperature (precipitation occurred), a stirred mixture of a saturated aqueous solution of sodium carbonate (200 ml) and ethyl acetate (200 ml) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 X 200 mL). The combined organics were washed with brine (100 mL), dried (Na2SO4), and concentrated under vacuum to give 3-cyano-8- (2,2,2_trifluoroethyl) _8_azepine. [3 · 2 · 1] Xin-2- 晞 (2.5 g, 35% yield). lH NMR (CDC13) · δ 1.60-2.40 (m? 5H), 2.60-2.80 (m, 1H), _____- 11 -_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1221842 A7 5 Description of the invention (9 3.10 (q, 2H), 3.45-3.65 (m, 2H), 6.75 (m, 1H) ppm. Quality 1 朁 Data: 216 (M +), 201, 187, 164, 147, ns, 110 〇Step 3 Connect a 10-liter round-bottomed flask to the reflux condenser and magnetic stirrer. The device is filled with nitrogen. 3-cyano-8- (2,2,2-trifluoroethyl) -8_acryl Bicyclo [3.2.1] oct-2--2- (0.216 g, 1 mmol) was added to the flask, and then methanol (0.5 ml) and pyridine (1.5 ml) were added to form a solution. Sodium borohydride Compound (0.046 g, 1.2 mmol) was added in a single portion, then the mixture was heated to 80 C 'and the reaction was maintained at this temperature overnight, refluxed for 3 hours, and then cooled to room temperature. Aqueous solution (10 mL) was added to the reaction mass, and the aqueous solution (pH 7) was extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2s04) and Empty Concentrated to give 3_cyano_8- (2,2,2-trifluoroethyl) -8-azabicyclo [3.2.1] octane (0.22 g, 74% yield), which is anisotropic Mixtures of structures (12 ·· 1 isotropy: axiality) 4 NMR (CDC13) (isoisomers): 5 1.5 0-2.15 (111, 8 «〇, 2.65-2.85 (m, 1H), 2.85 (q, 2H), 3.30-3 · 40 (m, 2H) ppm. Mass spectrometry data printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: 218 (M +), 199, 189, 164, 150. Example 2 This example Exemplifying the preparation of 3 · cyano-8_ (2,2,2-trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] octane. Step 1 Dry a 50 ml round bottom flask and connect to reflux Condenser and magnetic stirrer-12- This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) 1221842

5. Description of the invention (10) The device is filled with nitrogen. 3-cyano_8- (2,2,2-trifluoroethyl) _8-acylbicyclo [3.2.1] oct-2- (0 · 2ΐ6 g, 1 mmol) was added to the reactor After that, methanol (10 liters) was added. Magnesium filings (10 g, 40 mmol) were added in a single portion 'after 0.25 hours of induction period, and a violent reaction occurred, which was moderated by cooling in an ice bath. The mixture was stirred at 0 ° C, during which time the reaction was negative (due to the formation of methanol) and then returned to room temperature. The reaction mixture was then added to a solution of potassium dihydrogen phosphate (10 g) in water (4 (ml)) and stirred for 0.5 hours. Filter to remove residual solids, and the aqueous filtrate is extracted with ethyl acetate (3 X 20 φ liters). The combined organic layers were washed with brine (20 mL), dried (NadO4), and concentrated under vacuum to give 3-cyano-8 gas 2,2,2_trifluoroethyl). 8-azinebicycle [3.2 .1] Octane (0.16 g, 72% yield), which is a mixture of epimers (25:75 extroversion: introversion). HNMR (CDCl3) (isoisomers): δ 1.50-2.30 (m, 8Η), 2.85 (q, 2H), 2.90 (t, 1H), 3.30-3 · 40 (m, 2H) ppm. Mass spectrum data: 218 (M +), 199, 189, 164, 150. Example 3 This example illustrates the preparation of π 3-cyano-8- (2,2-difluoroethyl) · fluorazine bicyclo [3 21] octane. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. A 500-liter two-headed round-bottomed flask connected to a distillation head (short-path distillation) and a thermometer 2,5 —methoxytetrahydrocran (2 1 · 7 g, 〇 · 16 moles), hydrochloric acid (92 ml, 0.1 mole) and water (125 ml) were added to the flask. The mixture was heated to 120 ° C and maintained at this temperature until 40 ml of distillate was collected. The distillation head was replaced with a condenser and nitrogen, and the mixture was cooled to about 8. 〇. Acetic acid (22 · 5 ____ -13-

ΛΙ t ® g | ^ # ^ TcNS) A4 ^ m (210 X ^ 97 ^ JT 1221842 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (11 grams' 0.38 moles) added to the reactor Then, a solution of sodium hydroxide (28.9 g, 0.34 mol) in water (11 ml) was added over 0.25 hours. The reaction was cooled to 5 ° C. The acetone dicarboxylic acid (5 0.7 grams, 0.34 Modou) was added in portions, and a solution of difluoroethylamine hydrochloride (21.7 grams, 0.16 Moore) in water (50 liters) was passed through a dropping funnel After adding, SILCOLAPSE M5020τμ antifoaming agent (3 drops) was added to the reaction mass, and the amine solution was quickly added to the reaction mixture, keeping the temperature below 5. Stir the mixture at 0-5 t for 1 hour, return to room temperature and Keep overnight. Adjust the reaction quality to pH 6.5 by adding 47% alkaline soda solution. The aqueous solution is extracted with methane (3 x 90 ml). The combined organic liquid is salted (3 X 90 ml). 2M) extraction. After the acid washing solution is combined, 47% bacterial soda solution is added to adjust the pH to 7. The final aqueous solution is heated with digas. 3 X 90 ml) extraction, the combined organic liquids were dried (Mgs〇4), and concentrated under a vacuum to produce 8_ (2,2-difluoroethyl) _8_azepine bicyclic [3.2.1 ] Octano-3-one (2 8.6 g, 90 ° / 0 yield). The crude product (78_85. (: 0.2 mm Hg) was distilled to give a colorless oil (80% yield). H NMR (CDC13): δ 1.60-1.80 (m, 2H), 2.00-2.10 (m, 2H), 2.25 (d, 2H), 2.70 (dd, 2H), 2.95 (dt, 2H), 3.60 (brs, 2H), 5.95 ( tt, lH) ppm Quality data: 189 (M +), 160, 146, 132, 120, 96. Step 25 A 2-liter two-necked round bottom flask is connected to a pressure equalizing dropping funnel, a bubbler and Magnetic stirrer. 8- (2,2_difluoroethyl) -8_azabicyclo [3.21] octane-3_one (4.82 g, 25 mmol) was added to the reaction flask and suspended in water (5 ml ) Medium-14-Applicable to China National Standard (CNS) A4 size (21 ° '297 mm sauce) for paper size (please read the precautions on the back before filling this page) Order I22Γ842 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 V. Description of the invention (12), add hydrochloric acid (5 ml, 5M), and then add the solid Ammonium chloride (2.23 g, 4 1 mmol), stir the mixture until the ammonium chloride is dissolved (5 minutes). Cool the mixture to 5 ° C, potassium cyanide (5.03 g, 65 mmol) in water (7.5 亳) L) solution was added over 0.25 hours, after which the reaction was stirred at 0 ° C for 3 hours. After this time, the lower oil layer was separated from the solid precipitate / aqueous liquid layer, resulting in oily 3-cyano-3_hydroxy-8- (2,2-difluoroethyl) -8-azabicyclo [ 3 · 2 · 1] octane, which stands and darkens (5.32 g), the product is used directly in the next dish 0 Step 3 Dry a 50 ml three-necked round bottom flask connected to a reflux condenser, thermometer and magnetic Stirrer and introduce nitrogen. Phosphonium chloride (1.9 ml, 3.16 g, 24 mmol) and Pibidium (14.7 ml) were placed in a flask, and the mixture was cooled to -10 ° C in a propane / DrikoldTM bath. Add a portion of 3-cyano-3-hydroxy-8- (2,2-difluoroethyl-8-acylbicyclo [3 · 2 · 1] octane (2 g, assuming 9 millimoles' (Prepared from step 2), the final exotherm raises the reaction mass temperature to 55 ° C. The mixture is heated to 80 ° C and maintained at this temperature for 24 hours. When the reaction mass is cooled to room temperature, add ice / water ( 100 ml) of the stirred mixture. A deep mass was formed by the addition of solid sodium carbonate (6 g). The final aqueous solution was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were washed with brine (100 ml) and dried ( Na2S04) and condensing under tritium air to give 3-cyano-8_ (2,2-difluoroethyl) -8-acylbicyclo [3.2.1] octane-2-hydrazone (0.41 g, 13%) as a brown oil. Yield). Mass spectrometry data · 198 (M +), 169, 147, 132, 1 18, 105, 92 〇-15 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (please first Read the notes on the back and fill in this page] JT-1221842 A7 B7 V. Description of the invention (15) Examples This example illustrates 3 -cyano-8_ (2,2,2-trifluoroethyl) -8 vammabicyclo [3 · 2 1] of oct-2-ene Step 1. A 500 ml three-necked round-bottomed flask is connected to a large magnetic stirrer, thermometer, and hypochlorous salt bubbler. 8- (2,2,2_trifluoroethyl) _8-? Γbicyclo [3.21 ] Xin-3-S (10.56 g, 50 mmol) was added to the reaction flask, and then hydrochloric acid (5 M, 100 ml) was added to cool the mixture to 0 ° C. After the addition of diethyl ether (71 g), the mixture was stirred. 5 minutes. Hydrogenated bell (36.9 g, 550 mol) was added to the stirred reaction mixture in portions over a period of 0.5 hours. After the addition was complete, the 'final pink mixture was stirred at about 3 ° C for 3 hours. Hydrochloric acid (5M) was added to adjust the pH of the mixture to 5, water (50 ml) was added, and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2 × 100 ml). The combined organic extracts were dried (Na2S. 4) while leaving 3 · cyano-3-¾yl-8- (2,2,2-difluoroethyl) -8-acylbicyclo [3 · 2 · 1] octane solution in diacetic acid (3 2 8 ml) 'A sample of the solution (45 ml) was used directly in step 2. Step 2 Consumption cooperation with employees of the Central Standards Bureau of the Ministry of Economic Affairs printed and dried 100 ml three-necked round bottom The bottle was connected to a thermometer, a pressure-equilibrium dropping funnel, a magnetic stirrer, and a short-path distillation device. The device was filled with nitrogen. Phosphonium (9.09 g, 58.7 mmol) and pyridine (15.7 g) were added to the flask. , And then the mixture was cooled to _1 () in an acetone / DrikoldTM bath. 3_cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) -8 · azinebicyclo [3 · 2 · 1 A solution of octane in diethyl ether (45 ml, prepared in step 1) was added dropwise to the reaction mixture. The temperature of the 4 mixture was maintained below 10 ° C. Then heat the mixture-18- (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 1221842 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 2. Description of the invention (17) yl) -8 · Acyclobicyclo [3 · 2 · 1] octane in diethyl ether solution (303 ml). A portion of the solution (140 ml) was treated with sulfuric acid (3 drops of 98%), dried (Na2SO4) and concentrated under vacuum; and then 3-cyano · 3-hydroxy-8- (2 , 2,2-trifluoroethyl) -8-azabicyclo [3.2.1] octane (4.3 g), this material was used directly in step 2. Step 2 A dry 5ml two-headed round-bottomed flask was connected to a reflux condenser, a thermometer, and a magnetic stirrer. The device was filled with nitrogen. Phosphonium (1.34 g, 8.7 mmol) and pyridine (6.22 g) were added to the flask, and the mixture was cooled to -10 ° C in an acetone / DrikoldTM bath. 3-cyano-3-hydroxy · 8- (2,2,2-trifluoroethyl) · 8-acylbicyclo [3 · 2 · 1] octane (0.92 g, 3.9 mmoles-assumed, in (Prepared in step 1) was added as a part, and the final exotherm raised the reaction mass temperature to 12 ° C. The mixture was heated to 80 ° C and maintained at this temperature for 23 hours, after which the reaction mixture was cooled to room temperature. The reaction mixture was poured into ice / water (50 ml), and sodium carbonate was added in portions until the mixture was adjusted to pH 8. The final mixture was extracted with ethyl acetate (3 X 30 mL), and the combined extracts were dried (NaiSCU), filtered, and concentrated under vacuum to give cyano (2,2,2-trifluoroethyl) -8-acyl Bicyclo [3.2.1] octane-2_ 晞 (0.8 g, 72% of 8- (2,2,2-difluoroethyl) _8_pammabicyclo [3.2.1] oct-3-one Yield; 74:26 outward: inward cyano). Example 7 This example illustrates the preparation of 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) u "bicyclo [3 · 2 · 1] octane. Jacketed reactor, ground sodium cyanide (7.57 g, __ -20- This paper size is suitable for wealth and wealth (CNS) A4 size (210X297 mm)-t—ί WV ----- ^ " IiT ------ scale (please read the notes on the back before filling this page) 1221842 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 —--- B7 V. Description of Invention (22) [3 · 2 · 1] Preparation of octane. The split-neck jacketed reactor is connected with a stirring rod, a thermometer, a hypochlorite bubbler, and a pressure equilibrium dropping funnel. 8- (2,2,2-trifluoroethyl) -8-Azabicyclo [3 · 2 · 1] octan-3-one (3.04 g, 14.5 mmol) and diethyl ether (7 ml) were added to the reaction mixture. The reaction mixture was stirred and cooled to 0 t (Circulated ethylene glycol), and then ground sodium cyanide (1.07 g, 21.7 mmol) was added via a powder funnel. Hydrochloric acid (5M, 4.0 ml, 20.3 mmol) was added to the dropping funnel through Add to the reaction mixture over 5 minutes, and then stir the reaction mixture for hours. Hydrochloric acid (5M) was added to adjust the pH of the mixture from 9 to 5.5, the organic layer was separated, the aqueous layer was extracted with diethyl ether (2 X 30 ml), and the combined organic extracts were washed with diluted hydrochloric acid (30 ml, pH 6). Before drying (MgS04) and filtering, add sulfuric acid (98%, 2 drops) to the extract. Add 2 drops of sulfuric acid, and then concentrate the ether extract in vacuo to produce 3_cyanohydroxy_ 8- (2,2,2-difluoroethyl) -8-acylbicyclo [3.2.1] octane (72:28 outward: inward cyano) in diethyl ether as a gray-yellow solution. (Conversion by iHNMR analysis The rate is 83%.) Example 13 This example illustrates 3-cyano_3_hydroxy-8- (2,2,2-trifluoroethyl) -8_acylbicyclo [3 · 2 · 1] octane Preparation: The split neck jacketed reactor is connected with a stirring rod, a thermometer, a hypophosphite bubbler and a pressure-equilibrium dropping funnel. 8- (2,2,2-trifluoroethyl) _8_ 叮 二环 [3.2 .1] Octan-3-one (3.04 g, 14.5 mmol) and fluorobenzene (7 liters) were added to the reactor. The reaction mixture was stirred and cooled to 0 (circulated ethylene glycol), and then ground. Sodium cyanide (1.07 g, 21.7 mmol) via powder Leakage (Please read the back of the precautions to fill out this page)

) To hydrochloric acid (5M, 8 ml, 0.4 molar equivalent), and add another-part of hydrochloric acid (5M, 2 ml, U mole #) to the final mixture ^ toluene (25 ml) and water (25 4 liters). The organic layer was separated, and the aqueous layer was extracted with methylbenzene (2 X 25 ml) and the combined organic extracts were extracted. Sulfuric acid (98%, 4 drops) was added to the extract before drying (MgS04) and drying. A bucket of sulfuric acid was added to the toluene extract, and then concentrated under vacuum to produce the target compound as an off-white solid (20 g, 74% yield; 60:40 outward: inward cyano). Example 16 This example illustrates the preparation of 3-cyano-3-hydroxy_8- (2,2,2 • trifluoroethyl) _8_acylbicyclo [3 · 2 · 1] octane. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, the split neck jacketed reactor is connected with an overhead turbine stirrer, a thermometer, and a hypo-acid salt bubbler, 8_ (2,2,2-trifluoroethyl). Cyclo [321] octan-3-one (10.56 g, 50.0 mmol) and methanol (12 ml) were added to the reactor. The grain in the reactor was then cooled to 5 X with stirring; (circulated ethylene glycol), acetic acid (4.2 g, 70.0 mmol) was carefully added to the reaction mixture, and sodium cyanide (4.80 g, 95.0 millimoles) was added in portions via the powder funnel over ίο minutes. The reaction was stirred for 44 hours. Excess acetic acid was added to the reaction mixture 'and stirred for 16 hours. The toluene (20 ml) and water (20 ml) were added to the reaction mixture before the methanol was concentrated in vacuo (3 5). The residue was extracted with toluene (3 X 20 mL), and the combined organic extracts were washed with diluted hydrochloric acid (30 mL, pH 6). Before drying (MgS04) and filtering, add sulfuric acid (98%, 2 drops) to the toluene extract. Add 3 drops of sulfuric acid, and then the medicinal extract is concentrated in the air to produce a gray-brown semi-solid target compound-27- 1221842 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (25) 11.4 g '64% yield; 50 ·· 50 outward: inward cyano) 0 Example 17 This example illustrates 3 · cyano-8_ (2,2,2-trifluoroethyl) · 8_azabicyclo [ 3.2.1] Preparation of oct-2-ene. The two-necked round-bottomed flask is connected with an overhead paddle shaker, thermometer, condenser, nitrogen and hypogas generator. Phosphonium chloride (124 ml, mol) and Edo (97 ml, 12 (mol)) were added to the flask, and the mixture was cooled to -5 ° C. 3-cyano_8 • hydroxy-8_ (2,2,2-trifluoroethylazinebicyclo [3.2.1] -octane (14.0 g)) was added in part, and the final exotherm raised the temperature of the reaction mixture to 8 ° C. Heat the mixture to 80-88. (:, And 'maintain at this temperature for 24 hours before cooling to room temperature. Pour the reaction mixture into ice / water (200 mL), carefully add a saturated sodium carbonate solution and The mixture was adjusted to about pH 8. The mixture was extracted with ethyl acetate (3 X 200 ml), and the combined extracts were dried (Na2SO4), filtered, and concentrated under vacuum to yield the target compound (11.5 g). Analytical method (oxidation time, dichloromethane) and Kugelrohr steam oven (0.1 mm Hg '125-150. Purified the product to give the target compound (7.2 g, 99% purity) as a white pure crystalline solid. Example 18 This example illustrates the preparation of 3-cyano-8- (2,2,2-trifluoroethyl) · 8-acylbicyclo [3.2.1] octane. A three-necked round-bottomed flask was connected with an overhead and stirred away. The reactor was used for hydrogenation. The reaction flask was flushed with nitrogen for 0.25 hours, and then a palladium on carbon catalyst (5%, 50% slurry and water, 0.125 g, 0.03 millimolar), and the addition of 3-cyano--28- This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) --- Order 1221842 A7 ____________B7 V. Description of the invention (26) 8- (2,2,2 · trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] octane-2 · 晞 (0.50 g, 2.26 mmol) Ear) in toluene (25 ml). The reaction bottle was flushed with nitrogen and hydrogen. The reaction mixture was stirred at room temperature under hydrogen; dropped for 3 hours, and then maintained for 16 hours without stirring in nitrogen. Bottom) The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to produce the target compound (0.171 g), which is a mixture of epimers (88 · 13 axiality · isotropy). The product is ash Yellow oil, which becomes solidified after standing. Example 19 This example illustrates the preparation of 3-cyano-8 · (2,2,2-trifluoroethyl) · 8-acylbicyclo [3.2.1] octane. A round-necked flask was connected with an overhead stirrer for hydrogenation. The t-flask was flushed with rat gas for 0.25 hours. After that, a carbon-based catalyst (5%, 50% slurry and water, 0.068) was added. Grams, 0.016 millimolar), and added cyano-8- (2,2,2-trifluoroethyl) _8-acylbicyclo [3.2.1] oct-2- (3.40 g, 14.9 mol Ear) in toluene (19 ml). The reaction bottle was flushed with nitrogen and hydrogen. The reaction mixture was stirred at room temperature under hydrogen for 5 · 5 hours, and then maintained under nitrogen for 16 hours. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Add another part of the catalyst (0.070 g, 0.017 mmol), and then add toluene (1 ml) and methanol (1 liter). The reaction flask was stirred in thoron for 4.5 hours, and then maintained in nitrogen for 16 hours without stirring. Toluene (ml) was added), and the reaction was stirred under hydrogen for another 5 hours, and then maintained under nitrogen for 3 days. While toluene (19 ml) and methanol (1 ml) were added again, the reaction mixture was stirred under hydrogen for 7 hours and maintained under nitrogen for 16 hours without stirring. Add another portion of catalyst (〇136g, 032mmol), 1221842

Description of the invention (27) The reaction mixture printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs was stirred for another 7 hours, and maintained under nitrogen for 24 hours without stirring. 5. The catalyst was removed by filtration through Celitetm (under nitrogen), and the filtrate was concentrated under vacuum to produce the target compound (2.91 g), which is a mixture of epimers (85:15 axiality: isotropy). Example 20 This example illustrates the preparation of 3-cyano_8- (2,2,2-trifluoroethyl) _8_azabicyclo [m] octane. A three-necked round-bottomed flask was connected with an overhead stirrer for hydrogenation, and 3-cyano-8- (2,2,2 · trifluoroethyl) · 8-azinebicycle was added to the flask [3.2.1 ] Xin_ 2- 晞 (0.50 g, 2.26 mmol) and ethanol (35 ml). After the reaction flask was flushed with nitrogen, a carbon-free catalyst (5%, 0.005 g, 0.002 mmol) was added to water. The reaction flask was flushed with nitrogen and hydrogen, and the reaction mixture was room temperature. After stirring for 0.5 hours, the catalyst was removed by filtration through CELITETM (under nitrogen). The filtrate was concentrated under vacuum to produce the target compound (0.47 g, 69% reaction conversion) as an off-white crystalline solid, which was a mixture of epimers (8 (^ 20 axis: isotropic). The isolated product was redissolved In ethanol and continue the hydrogenation. The hydrogenated mixture and ethanol (35 ml) were added to the reaction flask, and the reaction flask was flushed with nitrogen. Palladium on carbon catalyst (5%, 0.025 g, 0.012 mmol) (Ear) was added to water, the reaction flask was flushed with nitrogen and hydrogen, the reaction mixture was stirred at room temperature for 4 hours, and then the catalyst was removed by filtration through Celitetm (under nitrogen). The filtrate was concentrated in the air to produce an off-white crystalline solid. Compound (0.45 g, 100% reaction conversion), which is a mixture of epimers (57:43 inward: external). _ -30- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297) Li) (Please read the notes on the back before filling this page)

1J -U 1221842 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (28) Example 2 1 This example illustrates 3-cyano_8 gas 2,2,2_trifluoroethyl) _8_acne Preparation of Bicyclic [321] Oct-2-ene. The three-necked round bottom flask was connected with a magnetic stirrer, thermometer, condenser, nitrogen and bubbler. Thionyl fluoride (2.1 ml, 0.028 mol) and p-pyridine (4.46 ml, 0.055 mol) were added to the flask. 3_cyano_3_hydroxy-8- (2,2,2_trifluoroethyl) -8_azabicyclo [3.2.1] -octane (5.05 g, 0.021 mole) and chloroform ( 20 ml) was added, and the final exotherm raised the temperature of the reaction mixture to 50 ° C. The mixture was stirred at room temperature for 1 hour, at 55x: 1 hour, and then refluxed for 1 hour. Additional thionyl chloride (2.1 ml, 0.028 mole) and pyrite (4.46 ml, 0.055 mole) were added to the flask, and the mixture was stirred at room temperature for another hour. The reaction mass was slowly poured into an ice / saturated sodium carbonate solution (200 ml) and the mixture was adjusted to pH 6 by adding another bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with methane (3 X 150 ml). The combined extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield the target compound (3.5 g, 47% yield). . Example 22 This example illustrates the preparation of 3-cyano-8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] by calcination. 3-cyano-8- (2,2,2-tricyanoethyl) -8-acylbicyclo [3 · 2 · 1] oct-2- (1 g, 4.6 mmol), toluene (8 Ml) and 5% palladium on carbon (0.02 g; Johnson Matt hey type 87L powder) were added to a stainless steel hydrogenation bottle (25¾ liters). Close the reaction bottle, flush with nitrogen, and replace nitrogen with 31 bar of hydrogen at 31 bar. This paper size is applicable to Chinese National Standard (CNS) A4 (21〇 > < 297mm) (Please read the precautions on the back before filling (This page)-Order 1221842 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (29) Gas. The reaction bottle was left standing for 10 minutes without being stirred, and it was confirmed that no gas leakage occurred. This system was switched on to hydrogen, the reaction mixture was heated to 50 ° C with stirring (350 rpm), and the reaction bottle was pressurized with hydrogen (400 psi). After no gas intake! The reaction mixture was stirred for 12 hours, and then allowed to stand overnight. The reaction bottle was purged with nitrogen and flushed with it. Samples used for column chromatography showed that 96% 3_cyano-8- (2,2,2-trifluoroethyl) _8-azinebicycle [3.2 .1] oct-2-ene. More palladium on carbon catalyst (0.02 g) was added to the reaction, and the reaction bottle was repressurized and reheated to 50 ° C. (: During the induction period! After hours, hydrogen uptake began, and 75 ml of hydrogen was absorbed within 2 hours. After heating and stirring for 5 hours, the reaction mixture was allowed to stand overnight. The reaction mixture was filtered to remove the catalyst The filtrate was evaporated under reduced pressure in a 50〇 bath. The last trace of the solvent was removed under oil pump pressure to produce the target compound as a colorless oil (yield 890 mg, inward cyano group 76/0, outward cyano group 2 〇0 / 〇). Example 23 This example exemplifies 3-exo-cyano_3 · intro_hydroxy · 8_ (2,2,2_trifluoroethyl) -8 · azabicyclo [3 · 2 · 1] Preparation of octane (isotropic cyano). A 250 ml jacketed flask is connected with an overhead stirrer, a thermometer and a puff gas bubbler. The flask is cooled to 0 t through a Haake circulating bath, and then hydrochloric acid is added. Aqueous solution (5M, 96.6 ml, 483 mol) and sodium cyanide (26.82 g, 531 mmol). Adjust 1 ^ to 90 with hydrochloric acid, and add 8 ^ (2, 2) in ι / 2 hours , 2-trifluoroethyl) _8_, Yabicyclo [321] xin_3_ (20.4 g, 97 mmol), the product precipitates during the addition period. Another 2 hours later has become pH 8.3, was added sodium cyanide (4.5 g) so that the pH became 91 in (TC continuously embrace the fall overnight. Water was added (⑽ mL), with hydrochloric acid

This paper scale is applicable to China National Standard (CNS) / ^ grid (21 () > < 7 public meals) 1221842 A7 B7 V. Description of the invention (30)-pH adjusted to 5.0. The formed pale brown precipitate was collected by filtration and taken out of methyl secondary butyl ether (100 ml). Sulfuric acid (98%, 3 drops) was added to stabilize the product. A small amount of brown aqueous material was decanted from the organic solution and concentrated under reduced pressure to produce 5.2 g of the target compound as brown crystals (22% yield at 96% strength). Example 24 This example illustrates 3-exo-cyano-3-intro-hydroxy · 8_ (2,2,2_trifluoroethyl) _8_acylbicyclo [3 · 2 · 1] octane (ie isocyanate Based). The 250 ml split necked jacket reactor was connected to an overhead stirrer, a thermometer and a salt gas bubbler. Water (50 ml) and sodium cyanide (13.42 g, 265 mmol) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy were added to the reactor, and the solution was cooled to 0 ° C. 8- (2,2,2-trifluoroethyl) -8-azabicyclo [3.2.1] octan-3-one (5.0 g, 24 mmol) and concentrated hydrochloric acid (22.1 g, 221 mmol) ) Are mixed, and the final brown hydrochloride solution is added to the reactor at 125 hours (via injection fruit), and an emulsion-colored precipitate is formed during the addition. The reaction mixture was stirred overnight, after which the pH was adjusted from 8.7 to 4.8 with hydrochloric acid. Diacetic acid (40 ml) was added (the pH dropped to 2 and adjusted to 5.6 with 70% sodium hydroxide). The organic layer was separated and the aqueous layer was extracted with another portion of diethyl ether (40 ml). The combined organic extracts were washed with pH 5.5 water (adjusted with hydrochloric acid), stabilized (2 drops of sulfuric acid), and dried () VIgS. 4), filtered, re-stabilized and concentrated under reduced pressure to produce a brown water wet semi-solid. This material was redissolved in diethyl ether, dried (MgSCU), filtered, and concentrated under reduced pressure to give the title compound as a beige solid (3.0 g, 85% strength ' 45% yield). ____- 33- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 1221842 A7 __B7 V. Description of the invention (31) Example 25 This example illustrates the cyano group 3 / cyano group by the axial / isotropic _3 _Hydroxy_8_ (2,2,2-trifluoroethyl) -8_leaf monocyclic [3 · 2 · 1] octane and 8_ (2,2,2-trifluoroethyl) yalicyclo [3 · 2 · 1] octyl 3-S and its mixture are converted into 3 -outward · cyano inward_Cyclo-8 · (2,2,2_difluoroethyl) -8-acylbicyclo [3 · 2 · 1] A mixture of octane (i.e., isocyano only) and 8- (2,2,2-difluoroethyl-8-azabicyclo [3,2 · 1] octane-3 · ketone. 50ml The neck-jacketed reactor was connected with an overhead stirrer, a thermometer, and a salt gas bubbler connected to the reactor. Sodium cyanide (0.75 g, 14.9¾ mol) and fluoride steel (1.15 g, 19.7 millimoles), hydrochloric acid (5M, 2.12g, 0.49¾ mole) and water (16ml). The reaction mixture was stirred and cooled to 0 ° C (Haake cycle unit). Axial / isotropic cyanocyanine was light. -8- (2,2,2-trifluoroethyl) · 8_acylbicyclo [3 · 21] octane (cyanohydrin) and 8_ (2,2,2-difluoroethyl) -8- Azabicyclo [3.2.1] octan-3-one Ketone) mixture (5.0 g) was added to the reactor in one portion. The progress of the reaction was detected by iH NMR and its progress is shown in the table below. After stirring at 0 ° C for 18 hours, the solution was mixed with hydrochloric acid. The pH of the reaction mixture was adjusted from 8.7 to 5.7. After filtering the product at 0 ° C (jacket filter), it was dissolved in diethyl ether and the remaining water was separated therefrom. Before drying (MgS04) and filtering, add Sulfuric acid (98%, 2-3 drops) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, and then add sulfuric acid (98%, 2-3 drops) and concentrate in the air to produce the target mixture (3.8 g). -34 -This paper size applies to Chinese National Standard (CNS) A4 (210X297 Meal) 1221842

Printed by the Consumers' Cooperative of the Central Prospectus Bureau of the Ministry of Economic Affairs, Invention Description (32)

26 This example exemplifies the preparation of 3-cyano_8 弋 2 2 9 ^, 2,2-difluorenylethyl) _8_azabicyclo [3 · 2 · 1] oct-2_ 晞 <.

A 50-liter three-necked round-bottomed flask is connected to the right side of the flask. A shiba stirrer, thermometer, nitrogen gas, and hypochlorite should be connected to it. ^ ^ · ^ J / S miscellaneous, in the reactor Add 3-extro-cyano · 3-intro-hydroxy-8- (2,2,2-trifluoroethyl) _8_azetabicyclo [3 21] octane (2 ^, 8.55 mmol) to acetonitrile (20 mL), and then added thionine (1.88 ¾ liter, 25.6 mmol) and pyridine (167 mL, 205 mmol). After stirring for 2¼ hours, the reaction mixture was cooled in a water bath by careful addition of water (10 mL). Aqueous sodium hydroxide (70%, 8.5 ml) was added to adjust the pH from 0.1 to 8 and then extracted with dichloromethane (2 x 25 ml). The extracts are combined, rinsed with water (25 ml), and dried (MgS04) -35- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling this page )

1221842 A7 ^ ---- ~~ __ B7 V. Description of the invention (33), filtration and concentration under reduced pressure, and the compound # & produces a compound of color oil (1.92 g, 76% Intensity, 84% yield, racemic mixture). Example 27-Example of this Example π When using thionine and different amines, solvents and stoichiometry to dehydrate 3-outward-cyano_3_inward-light-based_8_ (2,2,2_trifluoroethyl ) "" F-Bicyclo [3.2.1] is calcined to prepare 3_cyano_8_ (2,2,2-trifluoroethylazinebicyclo [3.2.1] oct-2- ". General procedure Chlorine (305 mg, 2.6 mmol) was added to 1 ml of acetonitrile in a test tube containing amine (0.25-2.5 equivalents), and 3_outward-cyano_3 • inward-hydroxyamidine (2,2,2 -Difluoroethyl) · 8-acylbicyclo [3.2.1] octane (300 mg, about 5000/0 strength, 0.64 mmol) in acetonitrile (2 ml) was added and the solution The reaction mixture was stirred at room temperature. This sample (3/4 ml) was added to an aqueous sodium hydroxide solution (3 ml, 0.5M). The final mixture was extracted with ethyl acetate (3 ml), and the organic layer was subjected to gas chromatography. (Gc) analysis, the results are listed in the following table, which shows the conversion to 3-cyano-8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3.2.1] oct-2- Percentage of hydrazone (product). Amount of amine Amount of time converted to product (equivalent) (hour) Percentage 0.25 12 11 Pyridine 1.1 1/2 30 Pyridine 1.1 2 65 Pyridine 2.5 1/2 58 -36- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page} Order蠓 Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, 1221842 A7 ___B7 V. Description of the invention (35) Gas was flushed three times, and nitrogen was replaced with hydrogen at a pressure of 3 bar. The reactor was left undisturbed for 10 minutes to confirm that there was no gas leakage Occurred. The system was switched on to hydrogen, the reaction was stirred to 50 ° C, and the reactor was pressurized to 3 bar with hydrogen. The reactor was stirred at 50 ° C for 12 hours (hydrogen uptake was monitored by Tressflow 'gas control unit) , And then cooled overnight. Another part of the catalyst (0.02 g, 0.018 mmol) was added to the reactor, followed by flushing with nitrogen and repressurizing with hydrogen. The reaction mixture was heated to 50 ° C and stirred After 9 hours, it was cooled to room temperature. The reaction mixture was carefully filtered through Celitetm to remove the catalyst, and the solvent was removed under reduced pressure to leave the target compound as a colorless oil (0.89 g, 85% yield, 97% gc Strength; axiality: isocyanic The mixture of basic isomers is 79: 21). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -38-This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1221842 A7 B7 V. Description of the invention ( 36) Chemical formula used in the narrative

R · (I)

, R *

R

Έ1 ㈧

Έ1

NC

III (III) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs • 39-(Please read the precautions on the back before filling out this page)

This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Application date H ", π Case No. 087119533 Category (the above sheds are filled out by this bureau) I. SS name Chinese Preparation 8-0 Yabi ring [3.2.1] Octane derivative method English PROCESS FOR THE PREPARATION OF 8 -AZABICYCLO [3.2.1] 〇CTANE DERIVATIVES Name Nationality 1. Douglas John Smith 2. Trevor Robert Perrier 3. Martin Charles Bowden 4. Stephen Martin Brown All are in the UK 4 " T Residence and residence 1.2 · All Jieqiang agrochemicals in Becknil District, Berkshire, UK 3.4 · A3, Lizi Road, Huddersfield District, West Yorkshire, UK 8 Name of the Sfe Factory (Name) British Merchant Xinjian Tower Co., Ltd. Nationality UK III. Applicant's residence and residence (office) Gulford, Sherry County, UK, Sherry Research Park European Centre, Presley Road Name of Representative Joanna Kamanchadler-1-Paper Size Applicable in China® National Standard (CNS) A4 (210 X 297 mm) 夂 .. $ |-·? F A4 • C4 Chinese Manual Replacement Page (January 1992) Yu Ming ----- Qin · patent specification! 22 丨 842

Controversy k A7 B7 Patent Application No. 087119533 Patent Specification Revised Page (June 91) V. Description of Invention (13)

The dried 10 ml round bottom flask was connected to a reflux condenser and a magnetic stirrer and placed under nitrogen. 3-cyano-8- (2,2-difluoroethyl) -8-acylbicyclo [3.2.1] oct-2-ene (0.17 g, 0.53 mmol) was added to the reactor, Subsequently, methanol (0.25 ml) and pibidium (0.75 ml) were added to form a solution. Solid sodium borohydride (0.039 g, 1.03 mmol) was added in a single portion, then the mixture was heated and refluxed for 3 hours. After cooling to room temperature, the reaction mass was poured into a stirred saturated aqueous solution of dihydrogen phosphate (10 ml). The aqueous solution was extracted with dichloromethane (3 × 10 ml), and the combined organic layers were dried (Na2S04) and concentrated under vacuum to give 3-cyano-8- (2,2-difluoroethyl) -8-acylbicyclo [3 · 2 · 1] Octane (0.197 g, 95% yield), which is a mixture of poor isomers (90:10 outward: inward). 4 NMR (CDC13) (exo isomer): δ 1.40-2.00 (m, 8Η), 2.50-2.80 (m, 1H), 2.60 (dt, 2H), 3.25 (m, 2H), 5.75 (tt 1H) ppm o Mass spectrum data · 200 (M +), 171, 149, 146, 132, 121, 105. Example 4 This example illustrates the preparation of 3.xyl-8- (2,2,2-trifluoroethyl acyclo [3 2 · 1] oct-2-ene. Step 1 50 ml three-necked round bottom flask Connected with magnetic stirrer, thermometer and hypochlorite bubbler. 8- (2,2,2-trifluoroethyl) -8-azinebicyclo [3 · 21] octane · 3 • one (1 · 06 Grams, 5 millimoles) was added to the reaction flask, and then hydrochloric acid (5M, -16- this paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) No. 087119533 amendment to the Chinese specification of the patent application Page (June 91 ^ B7 1. Description of the invention (彳 4 _ ~ 'preparation date Θ Nanqi 9ίυ 2-10 ml); cool the mixture to 0 ° C. After adding diethyl ether (7 g), The mixture was stirred for 5 minutes. Potassium hydride (3.69 g, 55 mmol) was added to the stirred and cooled reaction mixture in portions over a period of 0.25 hours. After the addition was complete, the final pink mixture was stirred at 5 ° C. 3 hours. 'Water (10 mL) was added, the organic layer was separated, and the aqueous layer was extracted with diethyl ether (2 × 10 mL). The combined ether extracts were dried (Na2S04), filtered and concentrated under vacuum to produce a dark 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3.2.1] octane (1.13 g) of color oil, which is left to solidify, And directly used in the step 2 drying 25 ml three-necked round bottom flask connected to a reflux condenser, a thermometer and a magnetic stirrer, the device was filled with nitrogen. Phosphonium chloride (1.41 g, 9.1 mmol) and pyridine (6.53 g) was added to the flask, and the mixture was cooled in acetone / 〇1 ^] ^ 〇1 (11 [^ bath to -10 ° C. 3-cyano-3-hydroxy-8- (2,2, 2-trifluoroethyl) -8-0 bicyclo [3 · 2 · 1] octamidine (0.97 g, 4.1 millimoles-assumed, prepared in step 1) was added in a portion, and the final exotherm improved the quality of the reaction The temperature was to 20 ° C. The mixture was heated to 80 ° C and maintained at this temperature for 24 hours, after which the reaction mixture was cooled and stirred at room temperature for 18 hours. The reaction mass was poured into ice / water (50 耄 L) and gradually Partially add solid sodium carbonate until the mixture is adjusted to pH 8. The mixture is extracted with ethyl acetate (3 x 30 ml), and the combined extracts are dried (NazSO4), filtered and concentrated in vacuo to give 3-cyano. -8- (2 , 2,2-trifluoroethyl) -8-azabicyclo [3.2.1] oct-2- (0.51 g, composed of 8- (2,2,2-trifluoroethyl) -8- 51% yield of azabicyclo [3 · 2 · 1] octan-3-one; 60 ·· 40 outwards ·· inward cyano). -17- This paper size applies to China National Standard (CNS) A4 specification (210X297 (Mm) " --- No. 087119533 Patent Application Chinese Specification Revised Page (June 91) Meeting 7 V. Description of the Invention (16) Plant No. 1-No. 2; Relying on iL · j to 80t, distillation Diethyl ether was reconnected to the condenser and refluxed. The reaction was maintained at 80 ° C for 24 hours, after which the reaction mixture was cooled and stirred at room temperature for 18 hours. The reaction mass was poured into ice / water (50 liters), and sodium carbonate was added in portions until the mixture was adjusted to pH 8 ·. The mixture was extracted with ethyl acetate (3 × 30 mL), and the combined extracts were washed with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated under vacuum to give 3- Cyano · 8- (2,2,2-trifluoroethyl) _8_azabicyclo [3.2.1] oct_2_associated (1.16 g, composed of 8- (2,2,2-trifluoroethyl ) 8-acylbicyclo [60% yield of 3.2 n-oct-3-one; 73:27 outward: inward cyano). This example exemplifies the preparation of 3-cyano-8- (2,2,2 · trifluoroethyl) -8 · azinebicyclo [3 · 21] oct-2-ene. Step 1 A 500 ml three-necked round bottom flask was connected with an overhead paddle stirrer, thermometer and hypochlorite bubbler. 8- (2,2,2-trifluoroethyl) · 8 · azinebicyclo [321] octan-3-one (10.82 g, 50 mmol) was added to the reaction flask, and then hydrochloric acid (5 M, ⑽ Ml); cool the mixture until generation. After the addition of diethyl ether (7 (8 g), 955 mmol), the mixture was stirred for 5 minutes. A gasification bell (36.9 g, 550 mmol) was added to the stirred reaction mixture in portions over a period of 0.5 hours. After the addition was complete, the final pink mixture was stirred for about 3 hours at about 3 hours. Hydrochloric acid (5M) was added to adjust the pH of the mixture to 58, and water (50 ml) was added to adjust the pH from 7 to 5.8. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2 × 100 ml). The acid extracts were combined and rinsed with highly diluted (ρΗ5.6) hydrochloric acid, leaving 3-cyano · 3 · hydroxy · 8_ (2,2, octatrifluoroethane-19-. This paper applies Chinese national standards ( CNS) Α4 Specification (210X297 mm) No. 087119533 Patent Application Chinese Specification Article 1YQ1 born on the 6th,

154.5 millimolar) was added to the reactor, and then 8 · (2,2,2 · trifluoroethyl) -8_azepine bicyclo [3 · 2 · 1] ocin-3-S was the same as (21.11 g, 96.6 millimoles) and n-butanol (48 ml). It was determined that all sodium cyanide was flushed into the reactor. Attach the lid of the reactor (which is connected with an overhead paddle stirrer and a thermometer), and connect the reactor to the hypochlorite bubbler. The reaction mixture was shaken and cooled to 0 ° C (circulated ethylene glycol). Hydrochloric acid (5M, 26.7 ml, 133.9 mol) was added to the reaction mixture through a syringe pump over a period of 2.5 hours. After the addition was complete, the reaction was stirred for 0.775 hours. "Add hydrochloric acid (5 M) to adjust the pH of the mixture from 9 · 5 p weeks to 3, water (200 ml) was added, and the pH of the mixture was adjusted to pH 1. The n-butanol layer was then separated. The acidic water layer was transferred to a three-necked round bottom flask, which was connected to an overhead paddle stirrer, thermometer, pH probe, and pressure-equilibrium dropping funnel. Toluene (100 ml) was added to the reactor, and the two-phase mixture was finally stirred vigorously. A saturated sodium bicarbonate solution was added dropwise over 0.25 hours, and the pH of the mixture was adjusted from 0.7 to 5.2. The organic layer was separated and the aqueous layer was extracted with toluene (2 × 100 ml). Before drying (MgSO) and filtration, sulfuric acid (98%, 5 drops) was added to the combined toluene extract. An additional 5 drops of sulfuric acid were added, and the toluene extract was concentrated under true 2 to give the target compound as an off-white solid (170 g, 65% yield; 65:35 outward: inward cyano). Example 8 This example illustrates the preparation of 3-synyl-3-meryl-8- (2,2,2-trifluoroethyl) -8-bicyclo [3 · 2 · 1] octane. Installed a split-neck jacketed reactor without cover, ground sodium cyanide (3.74 g, 76.3 Emole) was added to the reactor, and then 8 gas 2,2,2-trifluoroethyl was added 8- Acridine 21-This paper size applies to Chinese National Standard (CNS) A4 Specification (210X297 mm) Patent Application No. 087119533 ... Chinese Manual Correction Page (June 91) 4 I ... 〆 —____— ^ 一一 — ' r

V. Description of the invention (19 丨 HI ... '\ V .. Bu ,,-" · j ,.… "One by one ....: Bicyclo [3.2.1] octan-3-one (10.0 g '47.7 mol) and n-butanol (24 ml), make sure that all sodium cyanide is flushed into the reactor. Attach the lid of the reactor (which is connected with an overhead paddle stirrer and a thermometer), The reactor was switched on to a hypochlorite bubbler. The reaction mixture was stirred and cooled to -10 ° C (cyclic ethylene glycol). Hydrochloric acid (5M, 13.3 ml, 66.6 mol) was dripped through The funnel was added to the reaction mixture during 5-10 minutes. After the addition was complete, the reaction was stirred for an additional 21 hours. The pH of the mixture was adjusted from 9 to 3 by adding hydrochloric acid (5M), and water (100 ml) was added. The pH was adjusted again to pH 1. The n-butanol layer was then separated. The acidic rinse was transferred to a three-necked round bottom flask, which was connected to an overhead paddle stirrer, thermometer, pH probe, and pressure-equilibrium dropping funnel. Toluene (50 ml) was added to the reactor, and finally the two-phase mixture was vigorously stirred. A saturated sodium bicarbonate solution was added dropwise within 0.25 hours. The pH of the mixture was adjusted from 0.5 to 5.2. The organic layer was separated and the aqueous layer was extracted with toluene (2 × 50 ml). Before drying (MgS04) and filtering, sulfuric acid (98%, 3 drops) was added to the combined Toluene extract was added. After adding 3 drops of sulfuric acid, the toluene extract was concentrated under vacuum to give the target compound as an off-white solid (8.6 g, 69% yield; 67:33 outward-inward cyano group). Example 9 This example illustrates the preparation of 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] octane. Installation without cover Neck jacketed reactor, ground sodium cyanide (3.74 g, 76.3 mmol) was added to the reactor, and then 8- (2,2,2-trifluoroethyl) -8-azinebicycle [3 · 2 · 1] Oct-3-one (10.1 g, 48.3 mmol) and n-butanol (24 mmol-22-) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)

Patent Application No. 087119533 (Chinese version) (9 liters), confirming that all sodium cyanide was flushed into the reactor. Attach the lid of the reactor (which is connected with an overhead paddle stirrer and a thermometer), and connect the reactor to the hypochlorite bubbler. The reaction mixture was stirred and cooled to 0x: (cyclic ethylene glycol). Hydrochloric acid (5M, 13.3 ml, 66-6 mmol) was added to the reaction mixture over a 4 hour period via a syringe pump. After the addition was complete, the reaction was stirred for an additional 44 hours. Hydrochloric acid (5M) was added to adjust the pH of the mixture from 9 to 5.5, the organic layer was separated, the aqueous layer was extracted with toluene (2 X 30 ml), and the combined organic extracts were washed with diluted hydrochloric acid (30 ml, pH 6). Before drying (MgS04) and filtering, add sulfuric acid (98%, 3 drops) to the toluene extract. Three more drops of sulfuric acid were added, and the toluene extract was concentrated under vacuum to produce the target compound as an off-white solid (8-4 g, 52% yield; 57:43 outward-inward cyano group). Example 10 This example exemplifies the preparation of 3-cyano-3-meryl-8- (2,2,2-trifluoroethylabicyclo [3.2.1] octane. Installing a capless split neck jacket Reactor, unmilled sodium cyanide (390 g, 77.3 pen moles) was added to the reactor, followed by 8- (2,2,2-trifluoroethyl) -8-azinebicycle [3 · 2 · 1] Oct-3-one (10.1 g, 48.3 mmol), methyl tertiary butyl ether (24 ml) and water (10 ml), all sodium cyanide was determined to be flushed in In the reactor, install the lid of the reactor (which is connected with an overhead paddle stirrer and a thermometer), and connect the reactor to the hypochlorite bubbler. Stir the reaction mixture and cool to (cycle Ethylene glycol). Concentrated hydrochloric acid (5.73 ml, 67.1 mol) was added to the reaction mixture via a syringe pump over a period of 4 hours. After adding το 成, the reaction was stirred for another 28 hours. Hydrochloric acid (5M) was added to the mixture. Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 Patent Application No. 087119533 Chinese Manual Correction Page (June 91) V. Description of the invention (21 Rolling n 8 supplementary pH adjusted by 9 5.5. Separate the organic layer. Extract the aqueous layer with diethyl ether (2 X 30 mL). Rinse the combined organic extracts with diluted hydrochloric acid (30 mL, pH 6). Dry (MgS04) and filter before Sulfuric acid (98%, 3 drops) was added to the ether extract. After adding 3 drops of sulfuric acid, the ether extract was concentrated under vacuum to give the target compound as an off-white solid (81 g, 64% yield; 58: 42 Extroversion: inward cyano). Example 11 This example illustrates the preparation of 3-cyano-3- mesityl-8- (2,2,2-trifluoroethyl acyclo [3.2.1] octane. Neck separation The jacketed reactor is connected with a plunger, a thermometer, a hypochlorite bubbler, and a pressure-balanced dropping funnel. 8- (2,2,2-trifluoroethyl) · 8-8Ι 丫 二环 [3.2. 1] Sin-3_g (3.04 g, 14.5 mmol) and butyl acetate (7 liters) are added to the reaction benefit. The reaction mixture is then cooled and cooled to 0 (circulated ethylene glycol), and then ground Sodium cyanide (1.07 g, 21.7 mmol) was added via a powder funnel. Hydrochloric acid (5M, 4.0 ml, 20.3 mol) was added to the reaction mixture via a dropping funnel over 5 minutes. The reaction mixture was stirred for 29 hours. The pH of the reaction was adjusted from 9 to 5.5 by adding hydrochloric acid (5 M), the organic layer was separated and the aqueous phase was extracted with ethyl acetate (2 × 30 ml). The combined organic extracts were diluted with Rinse with hydrochloric acid (30 ml, pH 6). Add sulfuric acid (98%, 2 drops) to the extract before drying (MgS04) and filtration. Add 2 drops of sulfuric acid, and then remove the ether under vacuum. A solution of the target compound in butyl acetate is produced. Example 12 This example exemplifies 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethyl) _8_azabicyclo-24- This paper is sized to the Chinese National Standard (CNS) A4 (210X297) (Mm) '------ A7 B7 Patent Application No. 087119533 Revised Chinese Manual (June 91) V. Description of Invention (Yayi) ------------ 1 Hydrochloric acid (5M, 4.0 ml, 20.3 mmol) was added to the reaction mixture within 5 minutes via a dropping funnel, and the reaction was then stirred for an additional 3 hours. 1H NMR analysis indicated that 14% of the reaction conversion was 3.cyano _3_Hydroxy_8_ (2,22_trifluoroethyl) -8-azinebicyclo [3.2.1] octane. '' Example 14 This example illustrates 3-cyano-3-hydroxy-8- (2,2,2-Trifluoroethylazepine [3.2.1] octane production. — $ Split neck jacketed reactor connected with overhead turbine stirrer, thermometer and hypochlorite bubbler, 8 · (2,2,2 · trifluoroethyl) -8-azabicyclo [3.21] octane-3-one (10.89 g, 50.0 mmol), methanol (14 ml) and acetic acid (42 g, 7 〇〇mmol) was added to the reactor. The reaction mixture was cooled to 51 (circulated ethylene glycol), after which the ground potassium cyanide (5.37 g 80.0 millimolar) was added part by part through the powder funnel within 10 minutes. After the addition was complete, the reaction was stirred and the reaction was detected by NMR. After 44 hours of total reaction time, 84% of the NMR showed the target Compound (45:55 outward: inward cyano). Example 15 This example illustrates 3-cyano-3-hydroxy-8- (2,2,2-trifluoroethylazinebicyclo [3 · 2 · 1] octyl Preparation of alkanes. Split neck jacketed reactor is connected with overhead turbine stirrer, thermometer and hypochlorite bubbler, 8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] octanone (21.8 g '10 .00 mmol), methanol (28 liters), and ground cyanide ginger (10.42 g, 160.0 mol) were added to the reactor. Reaction mixture After cooling to 5 ° C (circulated ethylene glycol), acetic acid (4.2 g, 70.0 mmol) was added via a syringe pump over 3.5 hours. The reaction mixture was stirred and cooled (ice / water-26- 1221842 A7 B7 Chinese Patent Application No. 087119533 Revised Page (June 91) V. Description of the Invention (34 ΪΗ Q-1 Amine Amount (equivalent) Time (hour) Percentage of product converted to 2.5 2 91 0.25 1/2 17 mouth Kuilin 0.25 2 22 ττ Kuikoulin 1.1 1/2 35 mouth Kuilin 1.1 2 60 mouth Kuilin 2.5 1/2 59 mouth Kuilin 2.5 2 95 triethylamine 2.5 12 66 two Isopropylethylamine 0.25 12 15 N, N-dimethylaniline 0.25 1/2 12 4-dimethylaminopyridine 1.1 1/2 26 4-dimethylaminopyridine 1.1 72 32 4-dimethyl Aminopyridine 2.5 1/2 71 4-dimethylaminopyridine 2.5 72 78 Example 28 Ginger to carbon catalyst (5%, Johnson Matthey type 87L powder, 0.02 g, 0.018 mmol), 3-cyano -8- (2,2,2-trifluoroethyl) -8-acylbicyclo [3 · 2 · 1] oct-2- (2.91 g, 13 mmol) and toluene (8 ml) were added Into a 25 ml stainless steel ParrTM reactor, close the reactor. The device uses nitrogen 37- this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1221842 Patent Application No. 087119533 Chinese Patent Application Replacement (January 1992) 8 8 8 8 A B c D Λ Cinchou Specialty Benwei Bulletin to 1. A method for preparing compounds of formula (IV) • R1 / (IV) where R1 is Cw alkyl, CHdCu haloalkyl), benzyl, CH2 (C2_5 alkenyl) or CH2 (C2_5 alkynyl), including reduced compounds of formula (III): • R1 where R1 is as defined for the compound of formula (IV), the reduction is a mixture of an alcohol and a suitable metal; in an alcohol and, if necessary, in the presence of a suitable amine, an acid metal hydride; or a suitable metal Catalyst hydrogenation in the presence of a medium. 2. — A method for preparing a compound of formula (IV) according to item 1 of the scope of the patent application, wherein R1 is as defined in item 1 of the scope of the patent application and includes the following steps: i. Dehydration formula (II) using a suitable fluorenyl chloride (II) ) Compound: R1 is in a solvent in the presence of a suitable amine with a pka of 3-11, and it is suitable for the paper size. Applicable to China National Standard (CNS) A4 specifications (210X 297 mm) 1221842 A8 B8 C8 D8. 6. The temperature for patent application is ο -110 ° C. to prepare a compound of formula (III) in the first patent application range; and ii. reducing the compound of formula (III), the reduction is using a mixture of an alcohol and a suitable metal; neutralizing in an alcohol If necessary, use a metal oxide test compound in the presence of a suitable amine; or catalytic hydrogenation in the presence of a suitable metal catalyst. 3. · A method for preparing a compound according to formula (IV) in the first patent application, wherein R1 is as defined in the first patent application, and includes the following steps: i. Reacting with hydrogen cyanide in the presence of a suitable base to generate cyanide Acidified compound of formula VII: ⑴ to prepare the compound of formula (III); and ii. Reducing the compound of formula (III) in the scope of claims 1 or 2 of the patent application. 4. A method for preparing a compound of formula (IV) according to item 1 or 2 of the scope of the patent application, comprising the following steps: i. Reacting a compound of formula (I) with a mixture of an alkali metal cyanide and an inorganic acid in water at room temperature To obtain a compound of formula (π); ii. Reacting a compound of formula (11) with thionyl chloride or phosphonium chloride in the presence of said lake to obtain a compound of formula (III); and iii. Under anhydrous conditions In the temperature of 35-75 ° C and a pressure of 2-6 bar, in the presence of a palladium on carbon catalyst and an aromatic hydrocarbon solvent, the compound of formula (ΠΙ) -2- This paper standard applies to Chinese National Standard (CNS) Α4 Specifications (210X 297mm) 2 84 1X 2 12 8 8 8 8 AB c D 6. The scope of the patent application is reacted with hydrogen and reduced. Where R1 is 5. According to the method of claim 1, 2, or 3 (CHJCw haloalkyl). 6. — a compound of formula (II) or (III), ‘R1 where R1 is CH2 (C 1-3 function). 7. The compound of formula (II) or (III) according to item 6 of the scope of the patent application, wherein R1 is CH2CF3 or CH2CHF2. 8 · —a method for preparing a compound of formula (A), , R1 where R1 is Cm alkyl, CHdCu haloalkyl), benzyl, CH2 (C2 alkenyl) or CH2 (C2-5 block), and R2 is halogen, Ci-4 alkyl The oxygen-, cyano-, C2-4-methyl or C2-4-substituted P-pyridyl group includes the following steps: i. Reduction of the compound of formula (III) according to item 1 of the scope of patent application: 3- This paper applies to China National Standard (CNS) A4 (210 X 297 mm) 1221842 8 8 8 8 AB c D Patent application scope And R1 to obtain the compound of formula (IV) And, ii. Reacting a compound of formula (IV) with compound R2L in the presence of a suitable base, where L is a suitable leaving group. 9. The method according to item 8 of the application, wherein R1 is CH2CF3, and R2 is 5-chloropyridin-3-yl. 10. —A method for preparing a compound of formula (II): * R1 wherein R1 is as defined in item 1 of the patent application scope and is included in a suitable solvent, and the compound of formula (V) is: • R is in contact with a mixture of alkali metal cyanide and strong inorganic acid -4 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)